DESCRIPTION Abstract: Central cholinergic circuits exert powerful - though poorly understood - control over behaviors as diverse as attention, anxiety and sleep. Imbalances in cholinergic signaling underlie fundamental changes in personality and memory in neurodegenerative diseases. Indeed, the early signs of cognitive decline and heightened anxiety pathognomonic for Alzheimer's disease (AD) are thought to be due to loss of cholinergic signaling from the basal forebrain cholinergic nuclei. Shockingly little is known about endogenous ACh-mediated activity in the CNS. Cholinergic neurons are few in number, though extensive in their cortical projections. Even less is understood about how the non-directed release of this highly labile modulatory transmitter potently tunes circuit activity to match the degree of vigilance to the task and optimize performance outcome. The pharmacology of CNS cholinergic signaling remains obscure due to confounding effects on PNS function and poor selectivity of available drugs. Understanding the mechanisms of, and having the ability to control, the modulatory actions of ACh is the final frontier in the development of entirely new therapeutic approaches to neurodegenerative diseases such as AD. I will generate mice expressing optogenetic probes for selective activation or inhibition of cholinergic neurons in the Nucleus Basalis of Meynert, the major source of ACh inputs to cortex and amygdala. By titrating the light-induced activation vs. inhibition of NBM neurons with implanted fiber-optics, I will determine the profile of circuit activity and its modulation by endogenous ACh during task performance. I predict that by tuning the extent and timing of cholinergic activity, I will be able to control performance accuracy in attention-related tasks. My goal is to develop novel therapeutic approaches to Alzheimer's-associated cognitive decline. Targeted stimulation of CNS cholinergic nuclei via implanted optical probes combined with focal target-field delivery of cholinergic agonists will comprise a new era in treatment of CNS degenerative disorders.